Hit the brakes – a new perspective on the loop extrusion mechanism of cohesin and other SMC complexes

Abstract

The three-dimensional structure of chromatin is determined by the action of protein complexes of the structural maintenance of chromosome (SMC) family. Eukaryotic cells contain three SMC complexes, cohesin, condensin, and a complex of Smc5 and Smc6. Initially, cohesin was linked to sister chromatid cohesion, the process that ensures the fidelity of chromosome segregation in mitosis. In recent years, a second function in the organization of interphase chromatin into topologically associated domains has been determined, and loop extrusion has emerged as the leading mechanism of this process. Interestingly, fundamental mechanistic differences exist between mitotic tethering and loop extrusion. As distinct molecular switches that aim to suppress loop extrusion in different biological contexts have been identified, we hypothesize here that loop extrusion is the default biochemical activity of cohesin and that its suppression shifts cohesin into a tethering mode. With this model, we aim to provide an explanation for how loop extrusion and tethering can coexist in a single cohesin complex and also apply it to the other eukaryotic SMC complexes, describing both similarities and differences between them. Finally, we present model-derived molecular predictions that can be tested experimentally, thus offering a new perspective on the mechanisms by which SMC complexes shape the higher-order structure of chromatin.

The Interplay of Cohesin and RNA Processing Factors: The Impact of Their Alterations on Genome Stability

“…In addition to the function of cohesin in the regulation of sister chromatid separation [ 45 , 46 ], it also plays important roles in other cellular processes, such as DNA replication, DNA damage repair, the regulation of gene expression, and spatial chromosome organization [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Importantly, recent studies have suggested that cohesin also functions as a molecular motor, catalyzing the extrusion of DNA into the loops, and thus directly regulates genome organization [ 54 , 55 , 56 , 57 , 58 ]. Furthermore, a recent analysis of the genetic interactions between cohesin-complex-related genes and >1400 genes in the S. cerevisiae revealed 373 novel genetic interactions, suggesting the involvement of cohesin-related proteins in such biological processes as post-replication DNA repair, microtubule organization, and protein folding [ 59 ].…”

Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology

“…This led to the proposal of considering WABS and other cohesinopathies as ribosomopathies, a spectrum of rare diseases due to defects in ribosome biogenesis and function (see Figure 4) [81][82][83]. TAD boundaries are defined by the CCCTC-binding factor (CTCF), a sequence specific DNA binding protein that acts as a chromatin insulator [84]. A possible function of DDX11 in promoting cohesin loop extrusion activity has not yet been demonstrated.…”

“…An alternative theory about the molecular bases of WABS and other "cohesinopathies" is that these diseases could mainly derive from a dysregulated expression of genes that are critical for embryonic development [89]. Recent studies have revealed important functions of cohesin and the network of cohesin regulators/modifiers in organizing the chromatin loops (named topologically associating domains, TADs), which are believed to play a role in regulating gene transcription programs during development [84,90,91]. Global transcription alterations were described in CdLS and other "cohesinopathies" leading to the notion that they could be all disorders of transcriptional regulation or "transcriptomopathies" [92,93].…”

“…DDX11 cellular roles and related phenotypes observed in WABS patients. (A) Formation of chromatin TADs (topologically associating domains) in interphase cells is due to the loop extrusion activity of the cohesin-Scc2 complex.TAD boundaries are defined by the CCCTC-binding factor (CTCF), a sequence specific DNA binding protein that acts as a chromatin insulator[84]. A possible function of DDX11 in promoting cohesin loop extrusion activity has not yet been demonstrated.…”

Cryo-EM structure of the Smc5/6 holo-complex

“…For more expansive reviews of the SMC-family, including their respective functions and subunit compositions, please see: (Cutts and Vannini 2020; Datta, Lecomte, and Haering 2020; Hassler, Shaltiel, and Haering 2018; Matityahu and Onn 2021; Palecek 2018; Sole-Soler and Torres-Rosell 2020; Uhlmann 2016; Yatskevich, Rhodes, and Nasmyth 2019).…”